THE  CEREBROSPINAL  FLUID 


BY 

LEWIS  H.  WEED 


The  Anatomical  Laboratory,  Johns  Hopkins  University 


REPRINTED  FROM  PHYSIOLOGICAL  REVIEWS 
Vol.  II,  No.  2,  April,  1922 


4-. 


Reprinted  from  PHYSIOLOGICAL,  REVIEWS 
Vol.  II,  No.  2,  April,  1922 


THE  CEREBROSPINAL  FLUID 

LEWIS  H.  WEED 
The  Anatomical  Laboratory,  Johns  Hopkins  University 

It  is  obviously  impossible  within  the  limitations  of  this  review  to 
present  a  truly  comprehensive  account  of  a  characteristic  body-fluid  such 
as  the  cerebrospinal  liquid.  During  the  last  century  many  contribu- 
tions to  our  knowledge  of  this  fluid  have  been  made,  though  rather 
sporadically  and  with  long  intervals  between  publications.  Anatomists, 
physiologists,  pathologists  and  other  workers  have  studied  the  problems 
of  this  fluid;  the  proper  presentation  of  the  many  phases  of  the  subject 
would  lead  into  all  of  the  representative  biological  sciences.  But  during 
the  past  two  decades  contributions  of  a  physiological  and  anatomical 
nature  have  resulted  in  definite  enlargement  of  our  conceptions  of  this 
fluid  which  so  completely  fills  the  cerebral  ventricles  and  surrounds  the 
central  nervous  system.  It  is  largely  with  these  more  recent  advances 
in  knowledge  that  this  review  will  deal,  taking  from  the  older  literature 
only  those  contributions  which  have  founded  the  essential  bases  of  the 
biological  processes  of  the  cerebrospinal  fluid.  It  is  purposed  to  omit 
in  large  measure  the  exact  chemical,  pathological  and  serological  aspects 
of  the  subject  except  as  the  data  from  these  investigations  aid  in  estab- 
lishing the  fundamental  anatomical  and  physiological  phenomena  which 
have  to  do  with  this  fluid.  For  in  this  problem,  as  in  many  others,  it 
has  seemed  obvious  that  the  furtherance  of  investigations  upon  function 
has  depended  largely  upon  equivalent  advance  in  anatomical  knowledge. 

The  cerebrospinal  fluid,  as  first  effectively  described  by  Magendie 
(48),  is  a  clear  limpid  liquid  of  low  specific  gravity  (1.004  to  1.006), 
colorless,  and  of  a  slight  but  definite  viscosity.  When  withdrawn  during 
life,  the  liquid  usually  contains  but  few  cells  per  cubic  millimeter  (less 
than  10)  but  in  many  pathological  conditions  its  cell-content  may  be 
enormously  increased.  Various  estimates  of  the  amount  of  the  fluid 
existing  in  the  cerebral  ventricles  and  about  the  nervous  system  in 
adult  man  have  been  published;  the  computation  of  100  to  150  grams 

171 

PHYSIOLOGICAL   REVIEWS,   VOL.  II,  NO.  2 


737135 


172  LEWIS   H.    WEED 

given  by  Testut  (65)  is  probably  the  most  reliable,  but  because  of  the 
complexities  of  the  fluid-bed  the  figiires  should  necessarily  be  taken  as 
an  approximation. 

Chemifea-1  'examinations  have  demonstrated  that  the  cerebrospinal 
;'fiiiid  ;<?(intltiris  small  quantities  of  inorganic  salts,  of  protein  and  of 
'  dextrose; ' '  The  Inorganic  salts  are  chiefly  sodium  chloride  and  potas- 
sium chloride;  these  occur  in  the  ratio  of  17.3  to  1,  according  to  Mestre- 
zat  (50),  whose  monograph  is  a  compendium  of  analyses  of  both  normal 
and  pathological  fluids.  The  average  pH  value  is  given  by  Felton, 
Hussey  and  Bayne-Jones  (27)  as  7.75,  with  maximum  variations  of  7.4 
and  7.9.  Such  chemical  and  physical  characters  induced  Halliburton 
(37)  to  term  the  cerebrospinal  fluid  "an  ideal  physiological  saline  solu- 
tion," bathing  the  neurones  and  maintaining  their  osmotic  equilibrium. 
This  liquid,  then,  of  distinctive  constitution,-  unlike  other  body-fluids 
(except  the  aqueous  humor  of  the  eye)  becomes  the  subject  of  review. 
Definite  conceptions  regarding  its  circulation  are  current,  for  the  evi- 
dence today  points  to  a  constant  production  of  the  fluid,  its  passage 
through  the  cerebral  ventricles  and  thence  throughout  the  subarachnoid 
space,  and  its  subsequent  major  absorption  into  the  venous  system. 
Necessarily,  however,  these  conceptions  must  be  subjected  to  critical 
analysis,  to  determine  the  character  and  reliability  of  the  data  support- 
ing these  viewpoints.  For  this  purpose  it  becomes  essential  to  arrive 
at  some  understanding  of  the  anatomical  mechanisms  involved  and  to 
ascertain  the  functional  employment  of  these  structures  as  pathways  for 
the  cerebrospinal  fluid.  Such  a  discussion,  while  in  no  way  comprehen- 
sively covering  the  problems  of  the  cerebrospinal  fluid,  will  present  at 
least  in  part  the  phases  of  the  subject  which  have  in  recent  years  been 
most  extensively  investigated. 

THE  SOURCES  OF  THE  CEREBROSPINAL  FLUID 

The  description  of  the  glandular  histological  structure  of  the  choroid 
plexuses  by  Faivre  (25)  in  1853  marked  the  discarding  of  the  older  con- 
cept of  Haller  and  Magendie  that  the  cerebrospinal  fluid  was  a  product 
of  the  leptomeninges  (particularly  of  the  pia  mater) .  Faivre  made  the 
first  histological  survey  of  these  villous  projections,  showing  that  the 
cell  coverings  were  epithelial  in  nature  and  that  there  were  indications  of 
secretory  activity  in  these  cells.  Faivre's  observations,  supported  by 
similar  histological  descriptions  of  hyaline-like  inclusions  by  Luschka 
(47)  in  1855,  gave  origin  to  the  hypothesis  that  the  choroid  plexuses 
elaborate  the  greater  portion  of  the  cerebrospinal  fluid;  this  has  remained 


THE    CEREBROSPINAL    FLUID  173 

the  hypothesis  upon  which  most  of  the  investigations  regarding  the 
source  of  this  peculiar  body-fluid  have  been  based. 

The  purely  histological  evidence  presented  in  support  of  this  hypoth- 
esis, while  suggestive,  lacks  the  element  of  conclusive  proof,  though 
for  many  years  accepted  without  question.  During  the  past  twenty 
years,  however,  renewed  attempts  with  finer  histological  and  cytological 
methods  have  been  made  to  bridge  the  gap  between  intracellular  secre- 
tion-granules (vacuoles)  and  the  actual  production  of  the  liquid  sur- 
rounding the  cells.  Thus,  Findlay's  (28)  description  of  the  granular 
structure  of  the  normal  epithelial  cells  of  the  plexus,  with  frequent  in- 
clusions of  slightly  pigmented  globules  representing  the  fusion  of  smaller 
elements  and  staining  with  osmic  acid,  is  quite  typical  of  the  purely 
histological  demonstration  of  secretion.  Studnicka  (64)  obtained  some- 
what similar  evidence  of  secretion  by  the  cells  of  the  plexus  and  by  the 
ependymal  cells  of  certain  areas.  Pettit  and  Girard  (55)  found  hyaline- 
like  globules,  similar  to  those  described  by  Luschka,  in  the  cells  of  the 
plexuses  in  a  comprehensive  series  of  animals  but  did  not  feel  that  they 
represented  secretion-vacuoles.  Loeper  (46),  working  on  the  plexuses 
in  man,  described  pigmented  granules  and  other  granules  within  vacuoles 
staining  with  osmic  acid ;  he  stated  that  he  believed  that  such  histological 
findings  permitted  him  to  assert  that  the  cells  of  the  choroid  plexuses 
are  glandular.  Employing  methods  of  supravital  staining  in  addition 
to  the  ordinary  histological  procedures,  Schlapfer  (61)  concluded  that  the 
protoplasm  of  the  cells  of  the  choroid  plexus  contained  "  globoplasten" 
surrounded  by  a  lipoid-like  capsule;  his  histological  findings  offer  but 
little  additional  support  for  his  assertion  that  the  choroid  plexuses  se- 
crete the  cerebrospinal  fluid.  Galeotti's  (35)  description  in  rabbit  and 
mouse  of  three  different  intracellular  inclusions  (hyaline  droplets,  fuch- 
sinophilic  granules  and  small  basophilic  plasmosomes)  afforded  evidence 
of  cell-activity  by  the  choroidal  epithelium  but  did  not  demonstrate  the 
elaboration  of  the  liquid  by  these  structures.  The  same  statement  may 
be  made  of  Francini's  (32)  differentiation  of  two  forms  of  secretion- 
phenomena  in  these  cells — droplets  formed  in  the  cytoplasm  and  gran- 
ules derived  from  the  cell-nucleus.  Engel's  (23)  demonstration  of  a 
fuchsinophilic  granule  and  a  basophilic  granule  staining  with  methyl 
green  is  purely  histological  evidence  of  intracellular  inclusions  but  the 
great  variability  in  position  of  the  granules  can  hardly  be  interpreted 
as  indicating  different  phases  in  the  secretion-process.  And  there  is 
likewise  no  conclusive  proof  of  function  in  Hworostuchin's  (41)  descrip- 
tion of  the  changes  in  form  of  the  mitochondria  of  the  choroidal  epithe- 


174  LEWIS   H.    WEED 

Hum  as  showing  that  the  cells  play  an  active  role  in  the  elaboration  of 
cerebrospinal  fluid.  Yoshimura  (80),  in  a  histochemical  investigation 
of  the  cells  of  the  plexus,  believed  that  the  complicated  process  of  secre- 
tion of  the  cerebrospinal  fluid  was  related  to  the  aggregation  of  the 
smaller  cytoplasmic  granules  together  into  larger  vacuoles  for  discharge. 
Pellizzi's  (54)  hypothesis  that  the  epithelial  cells  of  the  plexuses  secreted 
granules  which  increased  in  size  by  absorption  of  the  fluid-plasm  until 
extruded,  was  based  on  a  comprehensive  study  of  the  plexuses  in  verte- 
brates and  may  likewise  be  considered  as  suggestive  support  of  the 
general  thesis. 

It  seems  clear  from  the  observations  just  detailed  that  while  the  many 
workers  upon  the  histological  structure  of  the  choroid  plexuses  have 
described  certain  granules  and  vacuoles  in  these  epithelial  cells,  there  is 
no  conclusive  evidence  that  these  intracellular  structures  constitute  the 
intracellular  mechanism  for  the  elaboration  of  cerebrospinal  fluid.  The 
difficulty  of  final  demonstration  that  these  granules  are  discharged  into 
the  fluid  or  are  in  some  way  dissolved  in  that  fluid,  cannot  at  present  be 
surmounted. 

But  fortunately  observations  of  a  far  more  conclusive  nature  have 
been  made  by  a  combination  of  pharmacological  and  histological 
methods.  Cappelletti  (9)  reported  in  1900  that  ether  and  pilocarpine 
increased  the  flow  of  cerebrospinal  fluid  from  an  experimental  fistula 
and  that  atropine  and  hyoscyamine  diminished  it.  While  considering 
that  the  differences  in  vascular  reaction  to  these  drugs  might  account 
for  the  phenomena  observed,  Cappelletti  felt  that  the  action  of  pilo- 
carpine as  a  general  stimulant  of  gland-activity  justified  the  assumption 
that  there  was  a  true  acceleration  of  secretion  of  the  cerebrospinal  fluid. 
Pettit  and  Girard  (55)  extended  these  observations  of  Cappelletti  by 
introducing  histological  examinations  of  the  choroid  plexuses  in  animals 
which  had  been  given  muscarin,  pilocarpine,  ether,  theobromine,  etc. 
The  administration  of  these  substances  was  found  to  increase  the  volume 
of  the  cytoplasm  of  the  choroidal  epithelium,  so  that  the  cells  became 
doubled  in  height.  Histological  study  of  these  enlarged  elements,  both 
in  the  fresh  and  in  fixed  material,  showed  that  the  cells  were  divided  into 
a  densely  granular  basilar  zone  and  a  clear  apical  zone.  While  the  clear 
apical  area  was  indicated  in  the  resting  cell,  the  rapid  enlargement  of 
this  zone,  under  the  influence  of  muscarin,  ether  and  theobromine, 
resulted  in  the  formation  of  a  distal  clear  vesicular  mass.  Such  a  dem- 
onstration of  histological  change  in  the  choroidal  epithelium  under 
the  influence  of  drugs  which  caused  an  increased  flow  of  cerebrospinal 


THE    CEREBROSPINAL    FLUID  175 

fluid  from  a  fistula,  was  believed  by  Pettit  and  Girard  to  prove  conclu- 
sively that  the  choroid  plexuses  possessed  a  secretory  function  in  the 
elaboration  of  cerebrospinal  fluid. 

Meek  (49),  repeating  the  experiments  of  Pettit  and  Girard,  came  to 
identical  conclusions.  Muscarin  caused  no  change  in  the  choroidal 
epithelium  in  the  rat  but  in  the  rabbit  and  guinea  pig  definite  alterations 
were  recorded.  Meek  stated  (p.  300)  that  "the  two  things  most 
striking  about  these  modified  cells  are  their  great  increase  in  height  and 
the  appearance  of  so  much  clear  space  at  the  distal  side  of  the  nucleus." 

While  the  observations  just  quoted  definitely  relate  the  choroid 
plexuses  to  the  elaboration  of  cerebrospinal  fluid,  there  is  available  other 
substantiating  evidence  in  support  of  this  hypothesis.  It  had  long  been 
realized,  from  pathological  examinations  of  cases  of  obstructive  internal 
hydrocephalus,  that  the  cerebrospinal  fluid  must  be  at  least  in  part 
produced  by  some  intraventricular  structure.  In  this  relationship 
renewed  attention  was  directed  to  the  choroid  plexuses  by  the  discovery 
by  Claisse  and  Levy  (12)  in  1897  of  a  case  of  internal  hydrocephalus  asso- 
ciated with  hypertrophy  of  these  intraventricular  plexuses.  Dandy  and 
Blackfan  (17),  (18)  and  Frazier  and  Peet  (33)  gave  additional  support 
to  the  general  contention  when  they  experimentally  produced  an  internal 
hydrocephalus  by  occlusion  of  the  aqueduct  of  Sylvius.  Cushing's  (14) 
observation  of  an  exudation  of  a  clear  fluid  from  a  choroid  plexus  ex- 
posed in  exploration  of  a  porencephalic  defect  likewise  added  suggestive 
substantiation  of  the  hypothesis.  Somewhat  more  tangible  proof  of 
intraventricular  elaboration  of  the  fluid  was  afforded  by  the  writer's  (68) 
demonstration  that  a  definite  and  sustained  outflow  of  cerebrospinal 
fluid  could  be  obtained  by  catheterization  of  the  third  ventricle  through 
the  aqueduct  of  Sylvius.  The  outflow  from  such  a  catheter  was  quite 
similar  in  amount  to  the  fluid  obtained  from  a  cannula  in  the  subarach- 
noid  space;  the  finding  argues  strongly  for  the  belief  that  the  major 
portion  of  the  cerebrospinal  fluid  is  produced  within  the  cerebral  ven- 
tricles. But  Dandy's  (16)  later  experiments  constitute  dependable 
evidence  not  only  that  the  place  of  production  of  cerebrospinal  fluid  is 
intraventricular  but  that  the  choroid  plexuses  are  the  responsible  struc- 
tures. Dandy  was  able  to  produce  a  unilateral  internal  hydrocephalus 
by  obstructing  one  foramen  of  Monro;  extirpation  of  the  choroid  plexus 
in  such  an  obstructed  lateral  cerebral  ventricle  prevented  the  develop- 
ment of  an  internal  hydrocephalus.  Dandy's  experiment  furnishes 
the  strongest  single  substantiation  of  the  hypothesis  that  the  choroid 
plexuses  elaborate  the  cerebrospinal  fluid. 


176  LEWIS    H.    WEED 

From  an  entirely  different  aspect,  also,  corroborative  evidence  in 
favor  of  the  choroidal  origin  of  the  cerebrospinal  fluid  is  found  in  em- 
bryological  observations  of  the  writer  (69).  In  a  study  of  the  develop- 
ment of  the  cerebrospinal  spaces  it  was  shown  that  the  first  extraven- 
tricular  expulsion  of  the  cerebrospinal  fluid  occurred  simultaneously 
with  the  first  tufting  and  histological  differentiation  of  the  ependymal 
cells  to  form  the  choroid  plexuses. 

The  evidence,  then,  from  histological,  pharmacological,  pathological 
and  embryological  standpoints,  surely  inclines  one  to  acceptance  of  the 
hypothesis  that  the  choroid  plexuses  of  the  cerebral  ventricles  largely 
elaborate  the  cerebrospinal  fluid.  It  does  not  seem  justifiable  to  accept 
the  evidence  from  any  one  standpoint  as  conclusive  for  many  of  the 
observations  recorded  are  corroborative  only.  Yet  the  general  histo- 
logical structure  of  these  plexuses,  the  cytoplasmic  inclusions,  and  the 
modification  of  the  cell-structure  by  pharmacological  agents  offer  more 
than  suggestive  substantiation  of  the  contention.  The  pathological 
studies  of  cases  of  internal  hydrocephalus,  the  direct  observations  of  the 
"sweating"  choroid  plexus,  the  embryological  relationship  between 
differentiation  of  choroid  plexuses  and  extraventricular  spread  of  the 
ventricular  fluid,  and  particularly  the  experimental  investigation  of 
unilateral  hydrocephalus,  when  considered  as  a  whole,  present  a  very 
strong  argument,  if  not  wholly  conclusive,  in  favor  of  the  view  that  the 
choroid  plexuses  are  the  elaborators  of  the  major  portion  of  the  cere- 
brospinal fluid.  It  does  not  seem  justifiable  to  discard,  as  Becht  (1) 
has  done,  all  of  the  evidence  in  favor  of  this  hypothesis  as  inconclusive. 
While  many  of  the  experimental  findings,  when  viewed  as  isolated 
observations,  may  be  explained  by  other  hypotheses,  the  great  mass  of 
data  cannot  be  interpreted  on  any  other  hypothesis  as  satisfactorily. 
Certain  of  Becht's  specific  objections  to  acceptance  of  the  theory  of 
origin  of  the  liquid  from  the  choroid  plexuses  have  been  answered  within 
the  last  year:  Wislocki  and  Putnam  (79)  demonstrated  by  histological 
methods  that  in  cases  of  experimental  internal  hydrocephalus  there  was 
absorption  of  foreign  solutions  through  the  ependymal  cells  lining  the 
ventricles  but  not  through  the  cells  of  the  choroid  plexus.  These  ob- 
servations were  confirmed  and  extended  by  Nanagas  (53),  who  showed 
by  similar  procedures  that  an  increased  intraventricular  absorption  of 
fluid  occurred  after  the  intravenous  injection  of  hypertonic  solutions  of 
sodium  chloride ;  in  no  case  was  there  absorption  of  the  fluid  by  the  cells 
of  the  choroid  plexus.  With  this  evidence  in  hand,  it  seems  justifiable 
to  disregard  Becht's  contention  that  the  cell-changes  in  the  choroid 


THE    CEREBROSPINAL    FLUID  177 

plexuses,  reported  by  Pettit  and  Girard  and  by  Meek,  may  as  properly 
be  interpreted  as  indicative  of  absorption  as  of  secretory  activity. 

But  even  as  a  working  hypothesis,  the  choroid  plexuses  must  not  be 
considered  to  be  the  sole  elaborators  of  the  cerebrospinal  fluid.  Ana- 
tomical evidence  presented  by  the  writer  (68)  indicates  that  the  perivas- 
cular  spaces  also  pour  a  certain  amount  of  fluid  into  the  subarachnoid 
space,  where  this  fluid  mixes  with  the  liquid  produced  in  the  cerebral 
ventricles.  Such  an  addition  to  the  cerebrospinal  fluid  probably  ac- 
counts for  the  reported  differences  between  subarachnoid  and  ventric- 
ular fluids  on  serological  and  chemical  analysis.  The  ependymal  cells 
lining  the  cerebral  ventricles  and  the  central  canal  of  the  spinal  cord 
may  also  contribute  even  in  the  adult  a  minimal  addition  to  the  intra- 
ventricular  cerebrospinal  fluid. 

Although  a  constant  elaboration  of  cerebrospinal  fluid  by  these 
mechanisms  is  indicated,  it  is  not  known  how  large  a  quantity  is  pro- 
duced in  any  given  time-interval  but  it  is  not  unlikely  that  the  majority 
of  computations  are  by  far  too  large.  Most  of  the  estimates  in  man 
have  been  based  on  the  amount  of  fluid  pouring  from  subarachnoid 
fistulae  (also  cases  of  cerebrospinal  rhinorrhea)  where  the  pressure, 
against  which  the  fluid  is  produced,  is  determined  solely  by  the  resist- 
ance of  the  abnormal  pathway.  The  same  lack  of  normal  conditions 
renders  unreliable  the  determinations  which  are  based  on  the  rate  of 
flow  from  experimental  cannulae  or  fistulae.  Estimations  of  the  produc- 
tion of  fluid  based  on  the  absorption  of  foreign  dyes  likewise  may  lead 
astray.  The  evidence  indicates,  however,  that  there  is  a  constant 
though  not  excessive  elaboration  of  the  cerebrospinal  fluid;  the  com- 
putations of  exact  quantities  thus  far  given  are  of  but  little  value. 

CIRCULATION   OF   THE    CEREBROSPINAL    FLUID 

The  cerebrospinal  fluid  produced  largely  by  the  choroid  plexuses  is 
poured  directly  into  the  cerebral  ventricles  which  are  lined  by  ectodermal 
ependymal  cells.  That  portion  of  the  fluid  formed  in  the  lateral  ven- 
tricles flows  through  the  foramina  of  Monro  into  the  third  ventricle  and 
thence  by  the  aqueduct  of  Sylvius  into  the  fourth  ventricle.  From  the 
fourth  ventricle  the  fluid  passes  out  into  the  subarachnoid  space;  there 
is  no  evidence  that  functional  communications  between  cerebral  ven- 
tricles and  subarachnoid  space  exist  elsewhere  than  in  this  region. 

The  exact  mode  of  escape  of  the  ventricular  cerebrospinal  fluid  from 
the  fourth  ventricle  into  the  subarachnoid  space  must  still  be  considered 
as  slightly  uncertain.  It  is  possible  that  the  inferior  velum  of  the  cere- 


178  LEWIS    H.    WEED 

bellar  roof  in  the  adult  is  an  intact  though  functioning  membrane,  as  in 
the  embryo;  the  existence  of  a  perforation  (the  foramen  of  Magendie) 
in  this  membrane  has  been  termed  an  artifact  because  of  the  dislocation 
of  structures  necessary  to  demonstrate  it  macroscopically  or  because  of 
the  shrinkage  of  tissues  in  embedding  for  histological  investigation.  The 
greater  weight  of  evidence  today  inclines  to  a  consideration  of  the  fora- 
men of  Magendie  as  a  true  anatomical  opening  in  the  velum — a  break 
in  the  ependyma  and  pia.  In  support  of  this  conception  of  a  true  fora- 
men between  fourth  ventricle  and  subarachnoid  space  may  be  quoted 
the  observations  of  Cannieu  (8)  and  of  Wilder  (78)  and  especially  the 
developmental  studies  of  Hess  (38)  and  of  Blake  (6).  Blake's  concep- 
tion of  the  formation  of  this  opening — a  shearing-off  of  the  base  of  a 
finger-like  evagination  of  the  rhombic  roof — is  rendered  more  certain 
by  recent  morphological  studies  of  this  region.  The  two  lateral 
foramina — those  of  Luschka — connecting  the  lateral  recesses  of 
the  fourth  ventricle  with  the  subarachnoid  space,  seem  to  have  as 
established  a  basis  for  their  existence  as  does  the  medial.  It  is 
through  these  three  foramina — or  surely  in  the  region  of  the  inferior 
tela  choroidea  if  through  an  intact  membrane — that  the  cerebrospinal 
fluid,  produced  in  the  cerebral  ventricles,  passes  into  the  subarachnoid 
space. 

From  the  cisternal  dilatation  of  the  subarachnoid  space  in  the  region 
of  the  medial  cerebello-bulbar  angle  the  cerebrospinal  fluid  slowly  seeps 
downward  in  the  spinal  subarachnoid  space  but  passes  more  rapidly 
upward  about  the  base  of  the  brain  and  thence  more  slowly  over  the 
hemispheres,  surrounding  the  whole  central  nervous  system.  This 
movement  of  fluid  is  facilitated  by  impulses  transmitted  to  it  by  the 
vascular  system;  in  the  spinal  region  there  is  also  an  almost  equivalent 
passage  of  fluid  upward.  The  subarachnoid  space,  in  which  the  fluid 
circulates,  is,  according  to  current  anatomical  descriptions,  contained 
between  the  arachnoidea  and  the  pia  mater.  Such  a  description  does 
not  present  a  proper  conception  of  these  fluid-containing  channels,  for 
it  seems  far  preferable  to  consider  the  subarachnoid  space  to  be  intra- 
leptomeningeal.  On  this  basis  the  arachnoid  may  be  described  as  the 
outer  continuous  membrane,  intact  and  fluid-containing,  from  the  inner 
surface  of  which  project  numerous  delicate  trabeculae,  which  merge 
with  the  pia  mater.  The  surfaces  of  the  arachnoid  membrane  and  of  the 
trabeculae  are  covered,  as  is  the  inner  surface  of  the  dura  mater,  by 
flattened,  polygonal  mesothelial  cells.  Identical  cells  also  clothe  the 
surface  of  the  brain  and  spinal  cord  to  form  the  essential  cell-covering 


THE    CEREBROSPINAL    FLUID  179 

of  the  pia  mater.  All  structures  (blood  vessels,  nerves,  etc.)  traversing 
the  subarachnoid  space  are  likewise  covered  by  these  mesothelial  ele- 
ments. The  cerebrospinal  fluid,  hence,  is  contained  within  a  completely 
cell-lined  system  of  continuous  yet  partially  interrupted  spaces  in  the 
meshes  of  the  arachnoid  trabeculae.  These  meshes  are  of  various  sizes, 
increasing  from  very  fine  reticular  spaces  over  the  cerebral  hemispheres 
to  more  widely  calibered  channels  in  the  cerebral  sulci  and  about  the 
spinal  cord,  and  reaching  their  maxima  in  the  cisternal  dilatations  about 
the  cerebello-bulbar  angle.  In  the  wide  channels  of  this  subarachnoid 
meshwork  the  cerebrospinal  fluid  is  obstructed  but  little  in  its  circula- 
tion, but  in  the  small  meshes  the  flow  of  the  liquid  is  slowed. 

Apart  from  their  established  function  as  efficient  fluid-retainers,  the 
cells  lining  the  subarachnoid  space  are  of  great  interest  because  of  their 
changing  morphology  under  different  physiological  conditions.  The 
writer  (70)  first  noted  that  these  mesothelial  cells  phagocyted  carbon 
granules  introduced  into  the  subarachnoid  space  and  that  when  phagocy- 
tic,  the  cells  increased  in  size.  Essick  (24)  then  showed  that  the  pres- 
ence of  foreign  material  (laked  blood,  granules,  etc.)  caused  these  cells 
to  become  enlarged,  vacuolated,  phagocytic  and  finally  detached  to 
form  free  macrophages  of  the  cerebrospinal  fluid. 

These  mesothelial  cells  likewise  have  importance  in  establishing  the 
relations  between  the  subarachnoid  and  the  perivascular  spaces,  for  there 
is  everywhere  in  the  central  nervous  system  a  distinct  fluid-containing 
space  about  each  of  the  perforating  blood  vessels.  The  cells  of  the  pia 
mater  turn  inward  to  form  an  outer  wall  of  such  a  perivascular  channel 
while  the  cells  of  the  arachnoid,  covering  the  vessel  as  it  traverses  the 
subarachnoid  space,  are  likewise  continued  inward  to  form  an  inner  cuff 
of  this  space.  Thus  each  blood  vessel  penetrating  the  nervous  system 
is  surrounded  by  a  cell-enclosed,  peri-adventitial  fluid-channel,  which 
communicates  directly  with  the  subarachnoid  space.  The  typical 
leptomeningeal  mesothelial  cell  of  this  channel  has  been  identified  for 
variable  distances  from  the  surface,  dependent  upon  the  caliber  of  the 
penetrating  vessel.  The  perivascular  fluid-channel,  when  the  mesothe- 
lial cell-cuff  ceases,  continues  inward  to  connect  directly  with  perineuronal 
spaces  about  the  nerve-cells.  These  ultimate  fluid-spaces  are  potential 
in  character  but  under  certain  circumstances  they  become  easily  rec- 
ognizable in  microscopic  preparations  (Mott  (52)).  While  originally 
termed  "lymphatic"  in  character,  these  perivascular  channels  have  no 
connection  with  the  lymphatic  system;  they  represent  however  an  im- 
portant accessory  fluid-system  of  the  cerebrospinal  axis,  affording  direct 


180  LEWIS    H.    WEED 

pathway,  uninterrupted  by  cell-membranes,  between  nerve-cell  and 
subarachnoid  space. 

Thus  far  mention  of  the  dura  mater  has  been  omitted,  for  it  has  but 
slight  relationship  to  the  cerebrospinal  fluid,  the  subdural  space  being 
anatomically  and  probably  physiologically  entirely  apart  from  the  sub- 
arachnoid.  But  in  one  respect  the  dura  mater  has  importance  in  the 
present  problem :  the  areas  of  penetration  of  the  dense  fibrous  tissues  of 
the  dura  by  the  arachnoid  represent  points  of  fusion  between  the  two 
membranes.  The  most  frequent  of  these  areas  of  penetration  are  the 
arachnoid  villi — prolongations  of  the  arachnoid  membrane  so  that  the 
arachnoidal  mesothelial  cells  come  to  be  directly  beneath  the  vascular 
endothelium  of  the  great  dural  venous  sinuses.  Identified  in  adult  man, 
in  infants  and  in  the  common  laboratory  mammals  (Weed  (66),  (67)), 
these  villi  are  covered  by  typical  arachnoid  cells,  usually  of  a  single 
layer  but  often  forming  whorls  and  presenting  double-layered  coverings. 
The  core  of  such  a  villus  may  be  a  strand-like  network  reduplicating  the 
subarachnoid  space  or  a  myxomatous  ground  work  simulating  the 
perimedullary  niesenchyme.  In  addition  to  the  true  arachnoid  villi, 
which  occur  in  the  walls  of  practically  all  of  the  dural  sinuses,  there  are 
found  infrequently  prolongations  of  the  arachnoid  into  the  dura  in  other 
situations.  The  arachnoid  villi  are  normal  structures;  the  great  enlarge- 
ment of  these  in  adult  life  results  in  the  formation  of  the  well-known 
Pacchionian  granulations. 

The  cerebrospinal  fluid,  then,  circulates  everywhere  about  the  central 
nervous  system— in  the  cerebral  ventricles  and  central  canal  of  the 
spinal  cord  and  also  in  the  tortuous  meshes  of  the  subarachnoid  space. 
These  channels  are  all  clothed  with  a  specialized  cell,  fluid-retaining  so 
that  a  true  circulation  of  fluid  may  be  maintained.  And  in  the  arach- 
noid villi  the  circulating  fluid  comes  into  close  relationship  to  the  great 
venous  sinuses  of  the  dura  mater. 

ABSORPTION   OF   THE    CEREBROSPINAL   FLUID 

With  the  evidence  indicating  a  constant  production  of  cerebrospinal 
fluid  and  a  circulation  of  the  liquid  through  the  cerebral  ventricles  and 
throughout  the  subarachnoid  space,  it  is  not  surprising  that  many  investi- 
gations should  have  been  undertaken  to  determine  the  mode  of  absorp- 
tion of  the  fluid.  The  experiments  performed  fall  naturally  into  two 
groups — the  physiological  observations  to  determine  whether  absorption 
of  the  fluid  is  into  venous  system  or  lymphatic  trunks  and  the  anatomical 
investigations  to  ascertain  the  exact  pathways  along  which  the  fluid  is 


THE    CEBEBROSPINAL    FLUID  181 

absorbed.  Because  of  the  great  importance  of  this  phase  of  the  subject 
the  evidence  will  be  given  in  some  detail. 

Modern  anatomical  studies  of  the  pathways  of  absorption  of  the  cere- 
brospinal  fluid  were  first  made  by  Key  and  Retzius  (43)  who  injected 
into  the  spinal  subarachnoid  space  of  a  cadaver  a  gelatine  solution 
colored  with  Berlin  blue.  While  the  pressure  used  was  somewhat  exces- 
sive (60  mm.  Hg.),  the  anatomical  continuity  of  spinal  and  cranial  sub- 
arachnoid  spaces  was  demonstrated,  for  the  whole  cranial  subarachnoid 
space  was  filled  with  the  gelatine-mass.  Furthermore,  the  gelatine  was 
traced  into  the  core  of  the  Pacchionian  granulations  along  the  great 
dural  sinuses,  and  through  the  cell-membranes  directly  into  these 
venous  sinuses.  Many  beautiful  plates  showing  this  passage  of  the 
injection-mass  but  giving  evidence  of  possible  rupture  are  presented  in 
Key  and  Retzius'  monograph.  In  addition  to  this  major  pathway  of 
absorption,  these  investigators  demonstrated  a  minor  accessory  absorp- 
tion of  the  fluid  into  the  lymphatic  system.  Quincke's  (56)  confirma- 
tory observations,  though  appearing  before  the  monograph  of  Key  and 
Retzius,  did  not  antedate  their  earlier  papers  on  the  subject.  Quincke 
injected  into  the  subarachnoid  space  of  living  animals  a  suspension  of 
cinnabar  granules  and,  killing  the  animals  at  varying  periods  thereafter, 
discovered  the  granules  almost  wholly  within  the  basilar  and  spinal 
subarachnoid  spaces,  for  the  most  part  held  by  phagocytic  cells. 
Granules  were  also  found  along  the  venous  sinuses  in  structures  which 
he  termed  Pacchionian  granulations;  in  the  cervical  lymph  nodes  like- 
wise particles  of  the  sulphide  were  identified. 

For  several  years  after  these  publications,  the  view  of  Key  and  Retzius 
was  accepted  as  establishing  the  anatomical  pathway  of  absorption  of 
the  cerebrospinal  fluid.  But  gradually  with  the  realization  that  Pac- 
chionian granulations  as  such  do  not  exist  in  infants  and  in  the  higher 
mammals,  it  was  felt  that  this  view  was  inadequate.  For  the  next  two 
decades  practically  no  work  was  done  upon  the  subject;  then  suddenly 
renewed  interest  in  the  problem  was  made  manifest  by  the  publication 
of  several  important  physiological  observations  demonstrating  a  major 
absorption  of  the  liquid  into  the  venous  system  and  a  minor  lymphatic 
drainage. 

Reiner  and  Schnitzler  (57)  injected  saline  solutions  containing  potas- 
sium ferrocyanide  into  the  spinal  subarachnoid  space  of  living  animals 
and  recovered  the  foreign  salt  in  from  30  to  40  seconds  from  the  blood 
of  the  jugular  vein.  Olive  oil  injected  under  similar  conditions  was 
identified  likewise,  though  the  blood  stream  was  slowed.  Reiner  and 


182  LEWIS    H.    WEED 

Schnitzler  stated  that  as  Pacchionian  granulations  do  not  exist  in  the 
animals  used,  other  pathways  of  absorption  must  exist.  Shortly  there- 
after Leonard  Hill  (39)  reported  that  saline  solution,  colored  with 
methylene  blue  and  introduced  into  the  subarachnoid  space,  could  be 
traced  "straight  into  the  venous  sinuses."  Within  a  few  minutes  (10 
to  20)  after  the  injection,  the  blue  was  identified  in  the  bladder  and 
stomach;  the  cervical  lymphatics  became  colored  only  after  an  interval 
of  one  hour.  Following  injection  of  potassium  ferrocyanide  into  the 
cerebrospinal  fluid,  Ziegler  (81)  detected  the  foreign  salt  in  the  posterior 
facial  vein  in  10  seconds  and  only  after  30  minutes  in  the  cervical 
lymphatics.  Similarly,  Lewandowsky  (44)  identified  sodium  ferrocya- 
nide in  the  urine  of  animals  within  30  minutes  after  intraspinal 
introduction. 

The  experiments  of  Spina  (63),  though  conducted  under  abnormally 
high  pressures,  likewise  add  support  to  the  idea  of  a  very  rapid  major 
venous  absorption  and  a  lesser  lymphatic  drainage.  Cushing's  (13) 
observations  on  mercury  and  non-absorbable  gases  led  him  to  hypothe- 
size a  valve-like  mechanism  for  drainage  into  the  venous  channel.  Both 
of  these  observers  commented  upon  the  absence  of  Pacchionian  granula- 
tions in  the  higher  mammals. 

Mott  (52)  in  1910,  from  study  of  the  brains  of  animals  subjected  to 
experimental  cerebral  anemia,  suggested  a  new  pathway  for  the  absorp- 
tion of  the  cerebrospinal  fluid,  based  on  the  occurrence  of  distinct  spaces 
about  each  nerve-cell,  connected  through  the  perivascular  channels 
with  the  subarachnoid  space.  Believing  that  this  fluid-system  contained 
cerebrospinal  fluid,  Mott  contended  that  normally  the  liquid  passes 
from  subarachnoid  space  into  cerebral  capillaries.  Cathelin  (10),  with- 
out supporting  data,  assumed  that  the  major  absorption  of  the  cere- 
brospinal fluid  was  into  the  lymphatic  system;  and  Goldmann  (36), 
employing  subarachnoid  injections  of  trypan  blue,  likewise  tentatively 
favored  this  view,  though  acknowledging  the  weight  of  evidence  in 
favor  of  the  major  venous  drainage. 

Dandy  and  Blackfan  (17)  in  1913  concluded  that  the  absorption  of 
cerebrospinal  fluid  was  a  "diffuse  process  from  the  entire  subarachnoid 
space,"  for  with  the  spinal  subarachnoid  space  isolated  from  the  cranial, 
they  found  "a  quantitative  absorption  proportionately  as  great  as  from 
the  entire  subarachnoid  space."  The  evidence  for  these  statements 
(18),  published  in  detail  a  year  later,  was  largely  based  on  the  excretion 
by  the  kidneys  of  a  readily  diffusible  dye — phenolsulphonephthalein — 
after  its  introduction  into  the  subarachnoid  space.  A  very  rapid 


THE    CEREBROSPINAL    FLUID  183. 

absorption  into  the  blood  stream  occurred  under  such  experimental  con- 
ditions while  the  lymphatic  drainage  was  minimal  in  amount  and  very- 
tardy.  After  subarachnoid  injections  of  india  ink,  Dandy  and  Blackfan 
were  able  to  find  no  anatomical  evidence  of  absorption  of  the  carbon 
granules — an  observation  in  accord  with  those  of  Quincke  (56)  and  of 
Sicard  and  Cestan  (62). 

It  was  with  these  contributions  as  a  background  that  the  writer  (66), 
(67),  (68)  began  his  anatomical  studies  of  the  absorption  of  the  cere- 
brospinal  fluid.  Critical  examination  of  the  preceding  work  was  con- 
vincing in  demonstrating  a  major  venous  absorption  and  a  minor  lym- 
phatic drainage  of  the  liquid,  but  the  reliable  data  were  practically 
entirely  physiological.  Thus  the  observations  regarding  the  rapid 
venous  absorption  of  readily  diffusible  substances  seemed  wholly  de- 
pendable but  the  anatomical  evidence  was  satisfactory  solely  in  demon- 
strating that  insoluble  particles  (cinnabar,  carbon)  did  not  leave  the 
subarachnoid  space  in  any  great  amount.  The  only  complete  morpho- 
logical investigations  were  those  of  Key  and  Retzius;  these  were  unsatis- 
factory because  the  injections  were  performed  on  dead  material,  the 
pressures  employed  were  high  (60  mm.  Hg.)  and  the  injection-mass  was 
a  viscous  colloid  (gelatine)  colored  with  Berlin  blue.  It  was  felt  that 
the  experimental  approach  must  be  such  that  a  subarachnoid  injection 
of  a  true,  isotonic  solution  of  non-toxic  foreign  salts,  capable  of  subse- 
quent precipitation  in  situ  for  histological  examination  and  not  diffusely 
staining  cellular  material,  could  be  made  in  the  living  animal,  under 
pressures  not  greatly  in  excess  of  the  normal.  With  these  criteria 
established,  experiments  were  undertaken  with  subarachnoid  injection 
of  potassium  ferrocyanide  and  iron-ammonium  citrate  in  isotonic 
solution  under  pressures  but  slightly  above  the  normal  (130-180  mm. 
H20).  Subsequently  the  central  nervous  system,  enclosed  in  meninges, 
was  fixed  in  an  acid  medium;  precipitation  of  the  foreign  salts  as  Prus- 
sian blue  permitted  adequate  histological  identification  of  the  pathway 
taken.  This  method  was  found  to  meet  all  of  the  standards  of  investi- 
gation set. 

The  experiments  were  carried  out  over  periods  of  several  hours  in 
living  anesthetized  animals,  with  introduction  of  the  isotonic  foreign 
solution  into  the  lumbar  subarachnoid  space.  The  spinal  and  basilar 
portions  of  the  subarachnoid  space  were  rapidly  filled  with  the  foreign 
solution  but  the  cerebral  portion  of  the  space  was  not  completely  in- 
jected until  the  experiment  had  been  continued  for  several  hours. 
Histological  examination  demonstrated  that  the  solution  had  not  pene- 


184  LEWIS   H.   WEED 

trated  any  of  the  cells  lining  the  subarachnoid  space;  the  precipitated 
granules  adhered  to  the  surfaces  of  the  cells  but  were  not  within  the 
cytoplasm.  The  foreign  solution  was  found  to  have  passed  directly 
into  the  venous  sinuses  by  way  of  the  arachnoid  villi  into  which  the  pre- 
cipitated granules  could  be  traced  from  the  cerebral  subarachnoid 
space.  These  granules,  representing  the  foreign  solution,  were  found 
within  the  mesothelial  cells  covering  the  villi  and  the  endothelial  cells 
lining  the  venous  sinuses,  as  well  as  within  the  lumen  of  the  venous 
sinus,  thus  demonstrating  the  essential  pathway  of  absorption.  In  no 
other  place  was  there  evidence  of  direct  passage  through  a  cell-mem- 
brane as  in  the  villi.  The  mechanism  of  passage  of  this  fluid  seemed 
to  be  a  process  of  filtration  from  a  point  of  higher  pressure  (subarachnoid 
space)  to  a  point  of  lower  pressure  (venous  sinus),  though  the  factors  of 
osmosis  and  diffusion  were  not  excluded.  The  absorption  of  true  solu- 
tions from  the  cranial  subarachnoid  space  was  shown  to  be  a  much 
more  efficient  and  rapid  process  than  was  the  corresponding  absorption 
from  the  spinal  subarachnoid  space.  Suspensions  of  particulate  matter 
were  found,  in  agreement  with  the  observations  already  recorded,  to  be 
retained  within  the  meshes  of  the  subarachnoid  space. 

In  addition  to  this  major  venous  absorption  through  arachnoid  villi 
directly  into  the  great  dural  sinuses,  an  accessory  drainage  by  way  of 
the  lymphatic  system  was  demonstrated.  This  seemed  a  much  slower, 
less  efficient  means  of  absorption  of  the  fluid,  caring  for  but  a  small 
fraction  of  the  total.  Such  lymphatic  absorption  was  wholly  indirect; 
the  fluid  reached  the  true  lymphatic  vessel  only  outside  of  the  dura  and 
then  by  way  of  perineural  spaces. 

These  anatomical  findings,  based  on  a  standard  of  experimentation 
which  approximated  the  normal,  agreed  largely  with  those  of  Key  and 
Retzius,  substituting  however  for  the  Pacchionian  granulation  the 
normal  arachnoid  villus.  Further  observations  were  made  to  ascertain 
the  truth  of  the  other  anatomical  hypotheses  ventured  for  the  absorption 
of  cerebrospinal  fluid :  thus,  no  structure  of  a  valve-like  nature  was  found 
in  many  examinations  of  serial  sections  of  the  great  dural  sinuses. 
Mott's  theory  of  absorption  by  cerebral  capillaries  was  excluded  by  the 
failure  of  the  injection-fluid  to  pass  into  the  peri  vascular  system  under 
conditions  approaching  the  physiological.  Dandy  and  Blackfan's  con- 
ception of  a  diffuse  absorption  by  the  vessels  of  the  subarachnoid  space 
was  likewise  found  untenable,  for  in  no  case  were  the  mesothelial  cells 
covering  these  vessels  penetrated  by  the  foreign  solution.  The  strongest 
argument  in  favor  of  the  diffuse  process  of  absorption  advanced  by 


THE    CEREBROSPINAL    FLUID  185 

Dandy  and  Blackfan  was  that  the  excretion  of  phenolsulphonephthalein 
from  the  isolated  spinal  subarachnoid  space  was  proportionately  as  great 
as  from  the  whole  cranial  and  spinal  subarachnoid  space.  The  tech- 
nique employed  by  Dandy  and  Blackfan  involved  withdrawal  of  an 
equivalent  amount  of  cerebrospinal  fluid  from  the  isolated  spinal  sub- 
arachnoid  space  before  injection  of  1  cc.  of  the  phenolsulphonephthalein 
solution.  The  writer  (67)  believed  that  this  substitution  could  not  be 
made  in  this  isolated  space  without  increase  in  the  spinal  subarachnoid 
pressure  and  escape  of  the  foreign  dye  into  the  epidural  tissues.  By 
reversing  the  experiment  he  was  able  to  show  that  absorption  of  phenol- 
sulphonephthalein when  introduced  into  the  cisterna  magna  was  as 
rapid  when  the  spinal  subarachnoid  space  was  excluded  as  with  the 
whole  cranial  and  spinal  subarachnoid  space  functioning.  The  cranial 
portion  of  the  nervous  system  seems,  therefore,  to  contain  the  efficient 
mechanisms  for  the  absorption  of  cerebrospinal  fluid. 

Since  the  publication  of  this  work  in  1914  there  have  been  other 
observations  regarding  the  absorption  of  the  cerebrospinal  fluid;  all 
accord  with  this  idea  of  a  major  venous  absorption  of  the  fluid.  Thus 
Frazier  and  Feet's  (33)  experiments  with  methylene  blue,  isamine  blue, 
trypan  red,  trypan  blue  and  phenolsulphonephthalein  demonstrated  the 
greater  importance  of  the  rapid  venous  absorption  and  the  lesser  of  the 
slow  lymphatic  drainage.  And  Dixon  and  Halliburton  (21),  in  the 
course  of  their  studies  of  the  cerebrospinal  fluid,  confirmed  this  general 
conception  of  the  process,  finding  no  escape  of  particulate  matter  from 
the  subarachnoid  space  but  a  free  and  rapid  absorption  of  true  solutions. 
Between  the  two  types  there  occurred  a  much  slower  absorption  of 
colloidal  solutions  than  of  true  solutions,  the.  larger  molecules  being 
absorbed  more  slowly  than  the  smaller.  They  concluded,  as  did  also 
Halliburton  (37)  that  "the  fluid  probably  reached  the  venous  sinuses 
by  way  of  the  microscopic  arachnoid  villi."  And  recently  the  writer,  in 
work  as  yet  unpublished,  has  repeated  certain  phases  of  his  original 
investigation  of  the  pathways  of  absorption,  with  continuous  observa- 
tions of  the  pressures  of  the  cerebrospinal  fluid  and  of  the  intracranial 
blood  vessels.  The  results  confirm  in  every  way  the  conception  of  the 
mechanism  here  presented. 

Thus  it  seems  fair  to  assume  that  the  absorption  of  the  cerebrospinal 
fluid  is  a  twofold  process,  being  chiefly  a  rapid  drainage  into  the  great 
dural  sinuses,  and  in  small  part  a  slow  indirect  escape  into  the  true 
lymphatic  vessels. 


186  LEWIS   H.    WEED 

THE   PRESSURE    OF   THE    CEREBROSPINAL   FLUID 

Practically  all  of  the  methods  of  recording  the  pressure  of  the  cere- 
brospinal  fluid  deal  with  connection  of  the  subarachnoid  space  to  an 
open  or  membrane  manometer.  It  is  very  difficult  with  any  of  the  pro- 
cedures to  avoid  the  loss  of  a  few  drops  of  fluid,  but  by  immediate  re- 
placement of  this  liquid  and  by  the  use  of  manometers  filled  to  the  esti- 
mated level  of  the  fluid,  the  pressures  obtained  by  these  simple  methods 
may  be  accepted  as  accurate. 

Very  few,  if  any,  of  the  early  records  of  the  pressure  of  the  cerebro- 
spinal  fluid  were  sufficiently  controlled  to  permit  direct  comparison  with 
the  data  obtained  by  recent  workers.  As  examples  of  the  variation  in 
the  pressures  recorded  by  the  earlier  investigators,  the  following  deter- 
minations may  be  given:  Key  and  Retzius  (43),  162  to  216  mm.  H2O 
in  inspiration  and  216  to  270  mm.  H2O  in  expiration,  in  etherized  dogs; 
Bergmann  (4,  5),  80  mm.  H2O  in  his  first  observations  and  in  his  second 
series,  120  to  160  mm.  of  salt  solution  in  narcotized  dogs;  Falkenheim 
and  Naunyn  (26),  100  to  150  mm.  H2O  in  curarized  dogs;  and  L/eyden 
(45),  80  to  150  mm.  and  100  to  120  mm.  H20  in  dogs  under  morphia. 
Leonard  Hill  (39)  believed,  however,  that  the  intracranial  tension  might 
vary  from  zero  to  50  mm.  Hg.  and  that  the  variations  reported  by  the 
earlier  observers  were  but  expressions  of  this  characteristic  of  the  intra- 
cranial pressure.1  Hill's  idea  of  variability  in  the  normal  pressure  of 
the  cerebrospinal  fluid  seemed  supported  by  the  observations  of  Dixon 
and  Halliburton  (20),  who  reported  40  to  70  mm.  of  salt  solution  as  a 
rough  average  of  the  normal  pressures  obtained  in  the  dog  under  mor- 
phine-urethane  anesthesia.  And  in  a  single  detailed  protocol  presented, 
the  pressures  at  5-minute  intervals  ranged  as  follows :  95,  25,  30, 35, 55, 
25,  80,  65,  65,  65,  75,  70,  60,  55,  50,  80,  90  mm.  of  10  per  cent  citrate 
solution. 

The  most  recent  work,  particularly  by  American  investigators,  has 
given  much  better  knowledge  of  the  range  and  variability  of  the  normal 
pressure  of  the  cerebrospinal  fluid.  Weed  and  McKibben  (75)  reported 
an  initial  average  of  119  mm.  of  Ringer's  solution  in  cats  anesthetized 
by  intratracheal  ether,  and  an  extreme  constancy  of  the  pressure  of  the 
cerebrospinal  fluid  under  such  experimental  conditions.  Becht  (1) 
found  considerable  fluctuation  in  the  pressure  of  the  fluid  in  etherized 
dogs  but  of  lesser  extent  than  did  Dixon  and  Halliburton;  his  average 

1  Within  the  limits  of  the  physiological  phenomena  investigated,  intracranial 
pressure  may  be  considered  to  be  identical  with  that  of  the  cerebrospinal  fluid. 


THE    CEREBEOSPINAL    FLUID  187 

pressure  of  112  mm.  (sodium  chloride  solution  of  specific  gravity  of 
1.088)  was  derived  from  39  dogs  under  intratracheal  ether.  Foley  and 
Putnam  (31)  presented  a  slightly  higher  average  of  127  mm.  for  the 
normal  reading  in  animals  under  ether  while  the  average  of  100  animals 
under  various  anesthetics  was  133  mm.  of  cerebrospinal  fluid;  no  com- 
ment upon  the  extent  of  normal  fluctuations  of  the  fluid  pressure  was 
made.  And  recently  Weed  and  Hughson  (72)  have  reported  an  average 
pressure  of  119  mm.  of  Ringer's  solution  for  77  cats  under  ether  by 
Woulfe  bottle;  the  fluctuations  in  the  pressure  under  the  experimental 
conditions  were  very  slight  in  extent  (11  mm.  in  an  animal  under  ob- 
servation for  2  hours). 

The  question  of  greatest  physiological  interest  in  this  phase  of  the 
general  problem  is  that  of  the  maintenance  of  this  pressure  of  the  cere- 
brospinal fluid.  All  of  the  conceptions  of  the  mechanism  for  the  main- 
tenance of  this  pressure  are  based  primarily  upon  the  rigid  character 
of  the  bony  coverings  of  the  nervous  system.  This  idea  that  the  cere- 
brospinal axis  is  situated  within  a  "closed  box,"  to  which  the  physical 
laws  of  such  a  system  apply,  was  first  advanced  in  1783  by  Alexander 
Monro  (51).  Monro  believed  that  the  substance  of  the  brain,  like  that 
of  other  solids  of  the  body,  is  nearly  incompressible  and  is  "enclosed 
in  a  case  of  bone,"  assuring  therefore  the  constancy  of  the  intracranial 
blood  content.  The  development  of  this  hypothesis  by  Kellie  (42)  in 
1824  led  to  wide  acceptance,  and  the  Monro-Kellie  doctrine  with  but  few 
alterations  has  served  as  the  basis  upon  which  the  physiology  of  the 
intracranial  contents  has  been  interpreted.  The  doctrine  was  modified 
by  the  introduction  of  the  cerebrospinal  fluid  into  the  consideration  by 
Burrows  (7)  under  the  influence  of  Magendie's  epochal  studies;  the 
hypothesis  was  then  formulated  by  Burrows  as  follows  (p.  32):  "the 
whole  contents  of  the  cranium,  the  brain,  the  blood  and  this  serum 
(cerebrospinal  fluid)  together,  must  be  at  all  times  nearly  a  constant 
quantity." 

Many  physiologists  have  subjected  this  Monro-Kelllie  doctrine  to 
experimental  proof  not  only  in  dead  but  in  living  animals;  while  diver- 
gent conclusions  have  been  arrived  at,  the  general  consensus  of  opinion 
expressed  in  the  literature  of  the  last  century  has  been  in  favor  of  the 
hypothesis.  And  in  the  hands  of  recent  workers  a  similar  unanimity 
of  expression  holds  though  occasional  investigators  express  doubt  as 
to  the  accuracy  of  the  premise.  Lately,  Weed  and  Hughson  (73)  have 
experimentally  demonstrated  the  essential  truth  of  the  doctrine  that 
(p.  99)  "the  bony  coverings  of  the  central  nervous  system  constitute 


188  LEWIS   H.    WEED 

within  tested  physiological  limits,  inelastic  and  rigid  containers;  the 
ordinary  physical  laws  of  a  'closed  box'  may  therefore  be  applied  to  the 
cranium."  And  with  appreciation  of  the  variability  in  volume  of  the 
constituents,  the  hypothesis  may  be  stated,  as  was  done  by  Weed  and 
McKibben  (76,  p.  553) :  "the  cranial  cavity  is  relatively  fixed  in  volume 
and  is  completely  filled  by  brain,  cerebrospinal  fluid  and  blood;  varia- 
tions in  any  one  of  the  three  elements  may  occur,  compensation  being 
afforded  by  alteration  in  the  volume  of  one  or  both  of  the  remaining 
elements." 

With  the  cranium  and  vertebral  column  serving  as  rigid  containers, 
the  relation  of  the  intracranial  vascular  pressures  to  the  pressure  of  the 
cerebrospinal  fluid  requires  immediate  consideration.  Current  physio- 
logical conceptions  of  these  intracranial  mechanisms  really  date  from 
the  work  of  Leonard  Hill  (39)  who  advanced  the  idea  that  intracranial 
pressure  is  (p.  71)  "the  same  as  cerebral  venous  pressure,  and  varies 
in  the  same  direction  absolutely  as  general  venous  pressure,  and  pro- 
portionately as  general  arterial  pressure."  Hill's  technical  procedures 
consisted  in  determing  cerebral  venous  pressure  in  the  torcular  Hero- 
phili  and  cerebrospinal  fluid  pressure  in  the  occipital  region. 

The  emphasis  placed  by  Hill  upon  this  equality  of  pressure  dominated 
physiological  opinion  for  over  fifteen  years;  it  was  not  until  the  publica- 
tion of  Dixon  and  Halliburton  (20)  in  1914  that  contradictory  evidence 
was  presented.  Using  experimental  procedures  essentially  similar  to 
those  of  Hill,  Dixon  and  Halliburton  demonstrated  that  the  cere- 
brospinal fluid  pressure  is  not  identical  with  that  of  the  dural  venous 
sinus,  and  stated  that  the  fluid  pressure  is  (p.  153)  "influenced  passively 
to  a  small  extent  by  changes  in  the  arterial  and  venous  pressures  but 
such  alterations  are  insignificant  compared  with  the  independent 
changes  in  pressure  which  occur  as  the  result  of  secretory  activity." 
These  investigators  also  showed  that  increase  in  the  cerebrospinal  fluid 
pressure  produced  a  passive  increase  in  the  cerebral  venous  pressure 
but  not  of  the  same  extent;  conversely,  alteration  of  the  cerebral  venous 
tension  caused  similar  though  not  identical  alteration  in  the  pressure 
of  the  cerebrospinal  fluid.  Under  normal  conditions  the  arterial  pres- 
sure was  found  by  Dixon  and  Halliburton  to  be  higher  than  the  intra- 
cranial venous  pressure  which  in  turn  was  always  higher  than  that  of  the 
cerebrospinal  fluid. 

Becht  (1),  employing  somewhat  similar  methods,  came  to  conclusions 
in  some  respects  at  variance  with  those  of  Dixon  and  Halliburton  though 
confirming  the  general  contention  of  inequality  of  cerebrospinal  fluid 


THE    CEREBROSPINAL    FLUID  189 

pressure  and  cerebral  venous  pressure.  Becht  stated  that  the  cerebro- 
spinal  fluid  pressure  was  dependent  upon  both  intracranial  arterial  and 
venous  pressures,  though  not  identical  with  either.  The  data  obtained 
indicated  that  either  the  cerebral  venous  (torcular)  or  cerebrospinal 
fluid  pressure  might  be  the  higher  but  that  usually  the  former  exceeded 
the  latter.  Passive  changes  in  the  torcular  pressure  were  found  to  affect 
the  pressure  of  the  cerebrospinal  fluid,  in  the  same  direction  but  not  to 
the  same  extent;  but  within  fairly  wide  limits  changes  of  the  cerebro- 
spinal fluid  pressure  were  not  believed  to  alter  the  pressure  of  the 
torcular. 

The  observations  of  these  recent  workers  were  all  carried  out  with 
.fairly  similar  technical  procedures,  particularly  for  the  determination 
of  venous  pressure  in  the  torcular  Herophili.  The  very  wide  divergences 
in  these  normal  pressures  (13  to  601  mm.  in  Becht's  series)  indicate 
that  the  method  is  subject  to  many  experimental  defects.  Weed  and 
Hughson  (74),  with  these  technical  disadvantages  in  mind,  devised  a 
simple  method  for  recording  intracranial  venous  pressure  in  the  superior 
sagittal  sinus  as  it  empties  into  the  torcular.  The  procedure  possessed 
the  very  distinct  advantage  of  permitting  direct  observations  of  the 
effect  of  the  manipulative  procedure  upon  the  pressure  of  the  cerebro- 
spinal fluid,  thus  affording  control  of  artificial  increases  in  the  pressure 
of  the  cerebrospinal  fluid  due  to  venous  obstruction  in  the  cranium. 
With  such  technical  controls,  Weed  and  Hughson  were  able  to  show  that 
in  practically  every  case  the  pressure  of  the  cerebrospinal  fluid  was 
considerably  above  (5-50  mm.)  that  of  the  sagittal  sinus.  They  also 
presented  data  which  indicated,  in  accordance  with  the  findings  of 
Dixon  and  Halliburton  and  of  Becht,  that  alteration  in  intracranial 
venous  pressure  effected  alterations  in  the  pressure  of  the  cerebrospinal 
fluid  in  the  same  direction  but  of  lesser  magnitude.  Conversely  it 
was  shown,  in  agreement  with  Dixon  and  Halliburton,  that  within  the 
physiological  limits  tested,  alteration  in  the  pressure  of  the  cerebrospinal 
fluid  caused  changes  of  lesser  extent  but  of  the  same  direction  in  the 
sagittal  venous  pressure. 

This  conception,  advanced  by  Weed  and  Hughson,  that  the  pressure 
of  the  cerebrospinal  fluid  is  practically  always  above  that  of  the  cerebral 
veins,  alone  affords  basis  of  explanation  for  Wegefarth's  experiments. 
Wegefarth  (77)  demonstrated  that  an  experimental  communication 
between  subarachnoid  space  and  superior  sagittal  sinus  remained  patent, 
without  hemorrhage  into  the  meningeal  cavities,  for  at  least  4  days. 
Removal  of  cerebrospinal  fluid  in  these  animals,  however,  resulted  in 


190  LEWIS   H.    WEED 

immediate  intrameningeal  hemorrhage.  Such  an  observation,  free  from 
the  errors  of  recording  instruments,  can  be  explained  only  on 'the  basis 
that  normally  the  pressure  of  the  fluid  is  above  that  in  the  sinus  or  that 
the  former  is  constantly  being  reduced  toward  the  latter. 

Analysis  of  the  reliable  data  concerning  these  normal  relationships 
seems  convincing  in  demonstrating  that  the  pressure  of  the  cerebrospinal 
fluid  practically  always  exceeds  that  of  the  superior  sagittal  sinus.  In 
no  sense  may  the  two  pressures  be  regarded  as  identical,  for  such  an 
identity  of  pressures  is  found  only  in  animals  in  which  the  technical 
procedures  have  resulted  in  the  production  of  direct  communications 
between  sinus  and  meningeal  spaces.  In  the  normal  animal  intracranial 
arterial  pressure  is  a  factor  of  importance  in  the  maintenance  of  the 
pressure  of  the  cerebrospinal  fluid,  though  slight  or  slowly  effected 
changes  in  this  arterial  tension  have  but  little  influence  upon  the  fluid 
pressure.  Thus  while  dependent  upon  both  intracranial  arterial  and 
venous  pressures  and  while  influenced  passively  and  in  the  same  direc- 
tion by  both,  the  pressure  of  the  cerebrospinal  fluid  may  be  considered 
to  be  relatively  independent  of  both  in  that  normally  it  maintains  an 
individual,  fairly  constant  level  far  below  that  of  the  intracranial 
arteries  and  somewhat  above  that  of  the  intracranial  veins. 

It  becomes  desirable,  then,  to  ascertain  the  factors  which  determine 
the  level  of  the  cerebrospinal  fluid  pressure,  but  in  this  inquiry  there  are 
practically  no  data  available  and  the  problem  becomes  speculative.  Yet 
it  is  instructive  to  think  of  the  cerebrospinal  fluid  as  being  largely  elabo- 
rated by  the  cells  of  the  choroid  plexuses  where  the  pressure  •  in  the 
blood  capillaries  is  estimated  at  from  40  to  60  mm.  Hg.  On  the  outer 
side  of  these  cells  is  the  cerebrospinal  fluid  with  its  pressure  of  110  to 
130  mm.  of  Ringer's  solution.  After  circulating  through  the  cerebral 
ventricles  and  subarachnoid  space  this  fluid  is  largely  returned  into  the 
venous  sinuses  of  the  dura  where  the  pressure  (as  determined  in  the 
superior  sagittal  sinus)  is  below  that  of  the  cerebrospinal  fluid  (as  de- 
termined in  the  cisterna  magna) .  On  such  a  basis  the  normal  mecha- 
nism for  the  absorption  of  this  characteristic  body  liquid  may  well  be  a 
simple  process  of  filtration  though  the  factors  of  osmosis  and  diffusion 
are  not  excluded  in  the  passage  of  the  fluid  through  the  cell-membrane 
of  the  arachnoid  villus.  No  determinations  of  the  pressure  of  the  cere- 
brospinal fluid  in  the  arachnoid  villus  have  been  made  but  it  is  unlikely 
that  this  pressure  is  markedly  different  from  that  of  the  cisterna  magna. 
Obstruction  to  any  part  of  the  pathway  of  the  fluid  results  in  raising 
intraventricular  tension  (cf.  Nanagas  (53))  thus  demonstrating  that 


THE    CEREBROSPINAL    FLUID  191 

cerebrospinal  fluid  can  be  produced  against  higher  pressures  than  nor- 
mally exist  in  the  cerebral  ventricles.  The  normal  pressure  therefore 
may  be  largely  determined  by  the  balance  between  the  constant  new 
production  within  the  cerebral  ventricles  and  the  absorption  into  the 
dural  sinuses :  this  pressure  of  the  cerebrospinal  fluid  becomes  dependent 
also  upon  intracranial  arterial  and  venous  pressures,  not  only  because 
of  the  relation  of  these  latter  pressures  to  the  production  and  absorption 
of  the  fluid,  but  because  of  the  constancy  of  volume  of  the  intracranial 
contents. 

MODIFICATION   OF   THE    PRESSURE    OF   THE    CEREBROSPINAL   FLUID 

During  the  past  ten  years  a  number  of  investigators  has  studied  the 
alterations  in  pressure  of  the  cerebrospinal  fluid  effected  by  the  intro- 
duction of  various  substances  into  the  blood  stream  or  alimentary  canal. 
The  subject-matter  naturally  differentiates  itself  from  the  purely 
mechanical  modifications  effected  by  pressure-changes  in  the  cerebral 
blood  vessels.  The  general  findings  in  this  latter  group  of  experiments 
have  been  presented  in  the  foregoing  section  of  this  review ;  the  pressure- 
changes  effected  in  the  cerebrospinal  fluid  by  solutions  of  various  con- 
centrations and  by  certain  pharmacological  agents  and  tissue  extracts 
will  be  discussed  here. 

Solutions  of  various  concentrations.  In  1919  Weed  and  McKibben  (75) 
reported  that  the  pressure  of  the  cerebrospinal  fluid  could  be  markedly 
altered  by  the  intravenous  injection  of  solutions  of  various  concentra- 
tions. It  was  shown  that  such  administration  of  strongly  hypertonic 
solutions  lowered  the  pressure  of  this  liquid  to  an  extreme  degree,  fre- 
quently producing  negative  values;  with  hypotonic  solutions  (distilled 
water)  a  prolonged  rise  in  the  pressure  of  the  fluid  was  obtained. 
Ringer's  solution  in  large  doses  produced  a  temporary  increase  in  the 
pressure  of  the  cerebrospinal  fluid,  followed  quickly  by  a  return  to  nor- 
mal levels.  Accompanying  these  changes  in  fluid  pressure,  Weed  and 
McKibben  (76)  found  marked  alterations  in  the  volume  of  the  brain, 
the  hypertonic  solution  producing  a  small  shrunken  brain  while  the 
hypotonic  solution  caused  an  outspoken  swelling  of  the  brain-substance. 
The  experimental  changes  in  brain  volume  were  particularly  pro- 
nounced in  animals  in  which  the  cranial  cavity  had  been  opened  by 
trephining. 

These  physiological  findings  have  since  been  abundantly  confirmed 
and  clinical  applications  of  the  phenomena  have  been  developed. 
Gushing  and  Foley  (15)  demonstrated  that  similar  alterations  in  the 


192  LEWIS   H.    WEED 

pressure  of  the  cerebrospinal  fluid  could  be  brought  about  by  the  inges- 
tion  of  hypertonfc  and  hypotonic  solutions.  Subsequently  Foley  and 
Putnam  (31),  after  verifying  the  original  conclusions,  studied  similar 
changes  in  the  pressure  of  the  cerebrospinal  fluid  which  were  effected 
by  the  intra-intestinal  administration  of  these  solutions  of  various 
concentrations.  And  Sachs  and  Malone  (60)  reported  observations 
upon  the  decrease  of  brain  volume  caused  by  the  intravenous  injection 
of  strongly  hypertonic  solutions.  In  addition  to  these  papers,  there  has 
appeared  a  number  of  reports  of  clinical  application  of  this  experimental 
modification  of  fluid  pressure  or  brain  bulk — notably  those  of  Gushing 
and  Foley  (15),  Sachs  and  Belcher  (59),  Ebaugh  and  Stevenson  (22), 
Foley  (30)  and  Hughson  (40). 

Recently  Weed  and  Hughson  (72),  (74)  have  extended  the  original 
observations  of  Weed  and  McKibben  (75);  in  addition  to  confirming 
the  initial  work  in  detail,  they  have  presented  data  showing  the  general 
systemic  and  intracranial  vascular  alterations  effected  by  these  agents. 
These  observations  were  made  over  periods  of  from  2  to  7  hours,  under 
adequate  experimental  conditions  in  which  the  pressures  recorded  (cere- 
brospinal fluid,  carotid  artery,  superior  sagittal  sinus,  superficial  bra- 
chial  vein)  remained  surprisingly  constant.  The  intravenous  injection 
of  a  large  quantity  of  Ringer's  solution  was  shown  to  cause  a  temporary 
rise  in  the  pressure  of  the  cerebrospinal  fluid  with  increases  in  both 
sagittal  and  brachial  venous  pressures,  the  former  being  the  greater. 
At  the  end  of  the  injection-period  all  of  these  pressures  tended  to  return 
to  their  previous  levels,  normal  pressures  customarily  being  attained 
within  30  minutes.  After  the  intravenous  injection  of  distilled  water 
in  similar  amount,  a  prolonged  rise  in  the  pressure  of  the  cerebrospinal 
fluid  occurred,  accompanied  by  alterations  in  both  sagittal  and  brachial 
pressures.  Both  of  these  venous  pressures  increased  during  the  period 
of  injection  and  for  a  few  minutes  thereafter,  the  sagittal  outstripping 
the  brachial;  within  30  minutes  these  pressures  were  usually  returned 
to  their  pre-injection  levels,  though  the  pressure  of  the  cerebrospinal 
fluid  was  still  elevated.  With  the  intravenous  injection  of  strongly 
hypertonic  solutions,  the  pressure-alterations  were  most  striking,  the 
cerebrospinal  fluid,  after  a  frequently  occurring  rise  during  the  interval 
of  injection,  dropping  markedly  and  often  exhibiting  extreme  negative 
values.  The  pressure  in  the  superficial  brachial  vein  rose  during  the 
period  of  the  hypertonic  injection  and  then  rapidly  resumed  its  pre- 
injection  level  or  a  new  level  slightly  below.  More  significant  were  the 
alterations  in  sagittal  venous  pressure:  here  the  reaction  during  the 


THE    CEREBROSPINAL    FLUID  193 

period  of  injection  depended  largely  on  the  reaction  of  .the  pressure  of  the 
cerebrospinal  fluid,  but  following  this  the  sagittal  pressure  was  always 
lowered  to  a  greater  extent  than  was  the  brachial  venous  pressure. 

These  experiments  afforded  a  unique  opportunity  for  study  of  the 
mechanisms  which  normally  control  the  pressure  of  the  cerebrospinal 
fluid.  Analysis  of  the  data  demonstrated  that  alterations  in  the  pres- 
sure of  the  cerebrospinal  fluid  could  be  effected  and  maintained  indepen- 
dently of  change  in  the  intracranial  and  systemic  vascular  pressures. 
The  most  striking  similarities  in  reactions  were  those  between  the  pres- 
sure of  the  cerebrospinal  fluid  and  that  of  the  brachial  vein  and  sagittal 
sinus;  after  the  injection  of  Ringer's  solution  or  of  distilled  water  they 
exhibited  somewhat  the  same  alterations,  differing  not  only  in  magni- 
tude but  in  duration.  After  the  intravenous  injection  of  hypertonic 
solutions,  however,  the  relationships  of  the  pressures  were  markedly 
altered,  with  the  pressure  of  the  cerebrospinal  fluid  profoundly  lowered, 
the  sagittal  venous  considerably  and  the  brachial  venous  but  little  if 
at  all.  Both  brachial  and  sagittal  venous  pressures  were  found  to  be 
lower  than  the  pressure  of  the  cerebrospinal  fluid  in  the  control- 
periods;  this  relationship  held  after  the  injection  of  isotonic  and  hypo- 
tonic  solutions  but  was  reversed  when  hypertonic  solutions  were  given. 
Arterial  changes,  when  slowly  brought  about,  caused  little  if  any  altera- 
tion in  the  pressure  of  the  cerebrospinal  fluid,  but  when  abrupt,  their 
influence  was  marked. 

The  changes  in  the  pressure  of  the  cerebrospinal  fluid,  effected  by 
the  intravenous  injection  of  solutions  of  various  concentrations,  must  in 
the  final  analysis  find  their  explanation  in  the  alteration  of  the  osmotic 
pressure  of  the  circulating  blood.  The  injection  of  a  large  volume  of  an 
isotonic  solution  was  followed  by  a  short-enduring  rise  of  the  cerebro- 
spinal fluid  pressure  which  subsided  in  approximately  the  same  time- 
interval  required  for  the  pressure-changes  effected  by  the  hypertonic 
and  hypotonic  solutions  to  reach  their  maxima.  The  usual  time  for 
maximal  reaction  of  the  pressure  of  the  cerebrospinal  fluid  was  noted 
to  be  from  25  to  35  minutes  after  the  end  of  the  intravenous  injection; 
in  this  interval  the  organism  was  attempting  to  compensate  for  altera- 
tion in  the  volume  and  salt-content  of  the  blood.  With  the  isotonic 
solutions,  the  compensation  was  one  for  increased  volume  of  fluid  only; 
this  compensation,  if  judged  by  the  time  of  return  of  the  cerebrospinal 
fluid  pressure  to  normal,  was  rapidly  achieved.  When,  however,  not 
only  the  volume  of  the  circulating  blood  was  increased  but  its  salt-con- 
tent relatively  diminished  as  by  the  intravenous  injection  of  distilled 


194  LEWIS    H.    WEED 

water,  two  processes  of  adjustment  proceeded.  The  blood  tended  to 
reestablish  its  normal  salt-content  by  passage  of  water  into  the  tissues 
and  possibly  into  some  of  the  body-fluids,  and  by  attraction  of  salts 
from  these  places;  and  it  also  tended  to  compensate  further  by  altera- 
tion of  the  vascular  bed.  The  increase  in  the  pressure  of  the  cerebro- 
spinal  fluid  and  in  the  brain  volume  may  be  taken  to  be  a  rough  index 
of  the  passage  of  fluid  from  blood  vessel  to  tissue;  the  return  of  the 
vascular  pressures  to  normal  levels  while  the  pressure  of  the  cerebro- 
spinal  fluid  remained  high,  indicated  the  completion  of  certain  of  the 
phases  of  readjustment.  In  the  readjustments  effected  by  the  organism 
to  the  injection  of  hypertonic  solutions,  there  were  somewhat  similar 
phases,  yet  differing  because  the  great  increase  of  fluid-volume  in  the 
circulating  blood  was  not  immediate  but  was  due  to  the  attraction  of 
water  from  the  body-tissues  and  possibly  from  the  body-fluids — a  phe- 
nomenon shown  by  the  decrease  in  brain  volume  and  by  the  reduction 
of  the  pressure  of  the  cerebrospinal  fluid. 

Such  an  explanation  of  the  phenomena  reported  leads  one  naturally 
to  a  consideration  of  the  role  played  by  the  osmotic  pressure  of  the  blood 
in  the  normal  process  of  absorption  of  the  cerebrospinal  fluid.  And 
intimately  connected  with  such  a  problem  is  that  of  the  volume  of  the 
brain  in  its  relation  to  the  intracranial  pressure.  At  the  present  time 
there  are  available  no  data  which  will  permit  of  exact  statement;  it 
must  be  realized  that  the  osmotic  changes  in  the  blood,  effected  by  such 
relatively  large  injections  of  solutions  of  various  concentrations,  are 
probably  beyond  the  ordinary  physiological  limits  of  change.  But  if 
one  may  judge  merely  by  the  anatomical  and  physiological  evidence 
afforded  by  subarachnoid  injection  of  isotonic  foreign  solutions,  osmosis 
and  diffusion  play  subordinate  roles  in  the  normal  process  of  absorption 
of  the  cerebrospinal  fluid  into  the  blood  stream. 

Pharmacological  agents  and  tissue  extracts.  Most  of  the  work  done  on 
this  subject  has  been  actuated  by  the  tenet  that  alteration  in  the  pres- 
sure of  the  cerebrospinal  fluid,  without  significant  change  in  intracranial 
vascular  pressures,  affords  a  more  reliable  means  of  determining  the 
effect  of  these  various  agents  upon  the  rate  of  production  of  the  fluid 
than  the  outflow  method.  While  logically  this  subject  should  perhaps 
be  discussed  under  the  heading  of  the  modification  of  the  rate  of  elabora- 
tion of  the  liquid,  it  may  properly  be  treated  here  as  an  experimental 
alteration  of  the  fluid  pressure. 

It  may  be  stated  at  the  outset  that  there  is  no  unanimity  of  opinion 
regarding  the  effect  of  either  pharmacological  agents  or  tissue  extracts 


THE    CEREBROSPINAL    FLUID  195 

upon  the  pressure  of  the  cerebrospinal  fluid,  without  significant  altera- 
tion in  intracranial  arterial  or  venous  pressures.  Dixon  and  Halli- 
burton (20)  found  that  extracts  of  the  choroid  plexus,  chloroform,  ether, 
urethane,  carbon  dioxide,  amyl  nitrite,  pilocarpine  and  other  drugs 
caused  a  "secretory  rise"  in  cerebrospinal  fluid  pressure  which  was 
independent  of  the  intracranial  vascular  alterations.  Becht  (1)  has 
investigated  the  subject  from  the  same  angle,  using  methods  somewhat 
similar,  and  has  stated  that  (p.  124)  "all  the  changes  in  the  fluid  pressure 
and  in  the  fluid  outflow  which  have  been  offered  as  proof  of  the  secretory 
mechanism  of  formation  of  the  cerebrospinal  fluids  can  be  traced  to 
alterations  in  venous  and  arterial  pressures  in  the  skull."  Similar  con- 
clusions have  been  reached  by  Becht  and  Matill  (3)  and  by  Becht  and 
Gunnar  (2). 

With  this  conflicting  evidence  it  is  of  course  impossible  to  do  other 
than  reserve  opinion  in  the  matter.  But  certain  aspects  of  the  con- 
troversy may  be  commented  upon.  Dixon  and  Halliburton  and  Becht 
determined  cerebral  venous  pressures  in  the  torcular  Herophili — a  meth- 
od which  because  of  the  wide  divergences  in  normal  pressures  reported 
does  not  seem  adequate  though  qualitative  changes  in  the  pressures  are 
probably  fairly  accurately  shown.  While  the  simple  manometric  meth- 
od has  been  modified  by  Becht  and  Gunnar  (2),  it  still  has  certain 
limitations  in  determining  a  true  change  in  rate  of  production  of  cere- 
brospinal fluid.  Of  these,  the  fact  that  the  normal  channels  of  absorp- 
tion are  intact  and  functioning  is  the  most  obvious  though  Becht  has 
minimized  the  weight  of  this  objection.  There  is  however  a  much 
more  formidable  disadvantage  in  that  the  manometric  method  cannot 
take  into  account  the  experimental  alteration  of  the  volume  of  the  brain. 
The  pressure-changes  in  the  cerebrospinal  fluid,  effected  by  the  intra- 
venous injection  of  distilled  water,  appear  to  fulfil,  after  the  period  of 
acute  vascular  change,  all  of  the  conditions  necessary  for  the  determina- 
tion that  the  injection  has  caused  an  increased  production  of  fluid — a 
markedly  elevated  cerebrospinal  fluid  pressure  with  intracranial  vascular 
pressures  at  the  pre-injection  levels.  The  outspoken  increase  in  brain 
volume  under  such  conditions,  however,  may  well  be  the  sole  explana- 
tion of  the  phenomenon;  until  the  experimental  variations  in  brain 
volume  are  more  fully  understood,  the  evidence  obtained  by  the  mano- 
metric method  should  be  accepted  only  with  reservations. 


196  LEWIS    H.    WEED 

MODIFICATION   OP   RATE   OF   OUTFLOW   OF   CEREBROSPINAL   FLUID 

That  certain  pharmacological  substances  may  modify  the  rate  of 
flow  of  cerebrospinal  fluid  from  a  cannula  introduced  into  the  subarach- 
noid  space  was  first  determined  by  Cappelletti  (9)  in  1900.  Employ- 
ing Cavazzani's  (11)  method  of  making  a  fistula  into  the  cistern  region, 
Cappelletti  showed  that  ether  given  by  intratracheal  tube  in  a  curarized 
dog  increased  the  rate>of  flow  of  the  fluid  from  0.15  to  0.35  grams  per  15- 
minute  interval  to  4.72  grams  for  the  same  interval.  A  second,  a  third 
and  a  fourth  administration  gave  momentary  increases  but  not  of  the 
same  extent  as  the  initial.  Similar  positive  results  were  obtained  with 
pilocarpine,  but  the  increases  though  obvious  were  not  marked.  Very 
slight  augmentation  of  the  rate  of  outflow  was  also  obtained  with  amyl 
nitrite,  while  atropine  and  hyoscyamine  caused  a  decrease  and  on  repeti- 
tion a  cessation  of  the  outflow. 

Pettit  and  Girard  (55)  immediately  confirmed  and  extended  these 
experimental  findings  of  Cappelletti,  including  in  their  studies  histologi- 
cal  examination  of  the  choroid  plexuses.  And  Meek's  (49)  observations 
were  likewise  entirely  confirmatory.  The  scope  of  the  investigation 
was  widened  in  1913  by  Dixon  and  Halliburton  (19)  who  studied  the 
effect  of  a  large  number  of  substances  upon  the  rate  of  outflow  of  cere- 
brospinal fluid  from  an  occipito-atlantoid  cannula.  They  were  able  to 
classify  the  substances  into  four  groups  according  to  their  effect  on  this 
rate  of  outflow,  placing  the  volatile  anesthetics,  alcohol,  carbon  dioxide 
and  extracts  of  choroid  plexus  and  of  brain  in  the  group  which  caused 
marked  increase  in  secretion.  Slight  increases  in  the  outflow  were  found 
to  be  caused  by  large  injections  of  water  or  of  normal  saline,  cholesterin, 
kephalin,  atropine,  pilocarpine  and  amyl  nitrite.  In  the  large  third 
group  of  substances  which  caused  no  increase  or  a  diminution  of  secre- 
tion were  included  extracts  of  the  pituitary,  of  mussel,  of  pineal  and  of 
pia  mater,  glucose,  urea,  lecithin,  etc.,  while  in  the  last  group  where  the 
effect  was  possibly  masked  by  vascular  or  respiratory  changes,  were 
muscarin,  pilocarpine,  adrenalin,  etc. 

Shortly  thereafter  Dandy  and  Blackfan  (18),  obtaining  cerebrospinal 
fluid  by  introduction  of  a  special  cannula  through  the  atlas,  found 
marked  accelerations  of  the  rate  of  output  of  cerebrospinal  fluid  follow- 
ing administration  of  ether  and  slight  augmentations  after  pilocarpine. 
With  amyl  nitrite  and  extracts  of  choroid  plexus  and  of  posterior  lobe 
of  the  hypophysis,  no  change  in  the  rate  of  output  of  the  fluid  was 
observed. 


THE    CEREBROSPINAL    FLUID  197 

Realizing  the  limitations  of  this  technique  in  that  the  normal  channels 
of  absorption  were  intact  and  that  the  intracranial  pressure  was  reduced 
to  the  resistance  of  the  needle,  Weed  and  Gushing  (71)  in  1915  cathete- 
rized  the  third  ventricle  and  studied  the  outflow  from  the  catheter 
whose  resistance  was  established  at  approximately  normal  pressure  of  the 
fluid.  In  addition,  cerebrospinal  fluid  was  obtained  by  callosal  and  oc- 
cipito-atlantoid  punctures  with  needles  of  similarly  standardized  resist- 
ances. Under  these  circumstances  the  intravenous  injection  of  extract  of 
posterior  lobe  of  the  hypophysis  was  found  to  increase  the  outflow  of 
cerebrospinal  fluid.  This  finding  was  explained  by  Dixon  and  Halliburton 
(21)  on  the  basis  that  the  hypophysial  extract  had  caused  a  contraction 
of  the  bronchioles  and  consequent  asphyxia.  Dixon  and  Halliburton 
used  an  intermittent  blast  for  their  artificial  respiration  while  Weed  and 
Gushing  employed  intratracheal  insufflation:  it  seems  questionable 
whether  this  explanation  of  the  finding  will  suffice. 

At  this  time  also,  Frazier  and  Peet  (34)  reported  that  brain-extract 
increased  the  secretion  of  the  cerebrospinal  fluid  as  determined  by  out- 
flow and  that  thyroid  extract  decreased  it,  independently  of  any  vascular 
changes. 

The  later  studies  of  the  effect  of  these  substances  upon  the  rate  of 
production  of  cerebrospinal  fluid  have  been  made  by  the  manometric 
method  and  have  been  discussed  in  the  preceding  section  of  this  review. 
The  limitations  of  the  outflow  method  were  realized  by  Weed  and  Gush- 
ing (71)  in  1915;  their  modifications  introduced  control  for  some  of  the 
sources  of  error  but  were  incomplete.  As  Becht  (1)  has  pointed  out, 
practically  all  of  this  work  is  of  no  scientific  value  because  of  failures  to 
record  simultaneously  the  intracranial  arterial  and  venous  pressures. 
Using  this  standard  but  employing  the  manometric  method,  Becht  and 
Matill  (3)  have  concluded  that  there  is  no  indisputable  evidence  that 
the  tissue  extracts  tested  have  a  specific  action  on  the  cerebrospinal 
fluid.  And  recently  Becht  and  Gunnar  (2)  reported  that  adrenalin, 
pituitrin,  pilocarpine  and  atropine  did  not  increase  the  production  of 
cerebrospinal  fluid,  as  determined  by  manometer  readings.  It  is  true 
that  the  method  of  recording  the  rate  of  outflow  of  cerebrospinal  fluid 
from  a  cistern  cannula,  even  with  careful  determinations  of  intracranial 
vascular  pressures,  yields  unreliable  data,  but  in  many  ways,  also,  the 
manometric  method  fails.  Both  of  these  methods,  which  at  the  present 
time  are  the  only  technical  approaches  to  the  problem,  are  of  question- 
able value  because  they  both  fail  to  take  account  of  the  experimental 
variation  in  brain-bulk.  When  a  method  which  will  permit  of  actual 


198  LEWIS   H.    WEED 

determination  of  this  variable  brain  bulk,  with  observations  also  of 
cerebrospinal  fluid  pressure  and  with  a  record  of  intracranial  vascular 
pressures,  is  devised,  data  of  conclusive  value  will  be  obtained.  And 
yet  one  cannot  but  lay  stress  upon  the  changes  in  the  choroidal  epithe- 
lium recorded  by  Pettit  and  Girard  (55)  after  the  injection  of  pilocarpine. 
Likewise,  as  first  reported  by  Cappelletti  (9)  and  since  noted  by  many 
workers,  the  rapidly  decreasing  responses  to  ether  and  pilocarpine  sug- 
gest strongly  that  the  accelerations  of  flow  of  cerebrospinal  fluid  under 
these  conditions  were  not  due  solely  to  vascular  alteration,  for  such 
ready  fatigability  would  not  seem  to  be  associated  with  a  vasomotor 
reaction. 

In  this  connection  it  is  interesting  to  speculate  upon  the  possibility 
of  modification  of  the  rate  of  elaboration  of  the  cerebrospinal  fluid,  after 
the  intravenous  injection  of  solutions  of  various  concentrations.  There 
is  as  yet  no  evidence  of  value  in  this  regard,  though  Foley  and  Putnam 
presented  data  which  suggested  that  after  the  injection  of  a  strongly 
hypertonic  solution,  a  new  ratio  between  the  rate  of  production  and 
absorption  of  the  cerebrospinal  fluid  became  established.  But  the  final 
elucidation  of  this  phase  of  the  problem  will  require  additional  work 
before  definite  conceptions  are  acquired. 

EELATIONSHIP   OF   CEREBROSPINAL   FLUID   TO   NERVOUS   SYSTEM 

Many  phases  of  the  relationship  existing  between  the  central  nervous 
system  and  the  cerebrospinal  fluid  are  of  utmost  significance  in  the 
present  discussion.  Filling  the  cerebral  ventricles  and  central  canal  of 
the  spinal  cord,  the  fluid  also  completely  surrounds  the  cerebrospinal 
axis  in  the  subarachnoid  space.  This  double  relationship  has  prompted 
many  observers  to  look  upon  the  cerebrospinal  fluid  as  constituting  a 
fluid-cushion  for  the  central  nervous  system  within  the  closed  system  of 
cranium  and  vertebral  column.  It  has  also  prompted  other  workers  to 
liken  the  cerebrospinal  fluid  to  the  lymph  of  the  nervous  system — a 
conception  which  in  the  light  of  present  knowledge  of  the  lymphatic 
system  is  untenable. 

Halliburton  (37),  in  a  recent  lecture,  declared  that  the  cerebrospinal 
fluid  serves  as  the  lymph  of  the  brain,  though  clearly  differentiating  it 
from  the  true  lymph  of  the  lymphatic  vessels.  It  seems  likely  that  such 
a  designation,  even  when  correctly  qualified  as  Halliburton  has  stated 
it,  is  apt  to  introduce  error.  All  modern  investigators  of  the  lymphatic 
system  are  agreed  that  true  lymphatic  vessels  do  not  exist  within  the 
dura  mater;  the  older  descriptions  of  such  lymphatic  vessels  were  actu- 


THE    CEREBROSPINAL   FLUID  199 

ally  descriptions  of  intradural  tissue-channels,  subpial  tissue-channels, 
or  arachnoidal  cell-columns  within  the  dura  mater.  As  Sabin  (58)  has 
pointed  out,  our  knowledge  of  the  lymphatic  system  has  advanced  so 
that  it  becomes  now  necessary  to  restrict  the  term  "lymph"  to  the  fluid 
contained  within  true  lymphatic  vessels  and  not  to  use  it  to  designate 
any  body-fluid. 

But  in  one  respect  the  cerebrospinal  fluid  does  function  as  an  acces- 
sory fluid  to  the  central  nervous  system.  In  foregoing  sections  the 
drainage  of  the  fluid  contained  within  the  perivascular  channels  toward 
the  subarachnoid  space  has  been  commented  upon;  this  fluid  really 
becomes  added  to  the  ventricular  cerebrospinal  fluid  in  the  subarach- 
noid space.  In  that  sense,  then,  these  perivascular  spaces  represent 
accessory  drainage  channels,  uninterrupted  by  cell-membranes  and 
capable  of  carrying  toward  the  subarachnoid  space  the  waste  products  of 
nerve-cell  activity.  Lacking  a  true  lymphatic  system,  the  nervous 
tissue  apparently  makes  use  of  these  perivascular  channels  as  pathways 
for  fluid  elimination. 

The  ultimate  connection  of  these  perivascular  channels  with  potential 
spaces  about  each  nerve-cell  indicate  the  close  relationship  between  the 
cerebrospinal  fluid  and  the  nervous  system.  And  in  addition  to  these 
rather  obvious  fluid  spaces  about  the  nerve-cells,  there  is  evidence 
indicating  that  this  fluid-system  is  intimately  connected  with  the  general 
tissue-channels  through  the  ground-substance  of  the  brain.  The 
general  direction  of  flow  of  this  fluid  under  normal  conditions  seems  to 
be  toward  the  subarachnoid  space. 

But  under  certain  conditions  this  direction  of  flow  may  be  reversed 
so  that  the  cerebrospinal  fluid  passes  from  subarachnoid  space  to  nerve- 
cell.  The  first  of  these  conditions  is  that  of  cerebral  anemia  in  which, 
as  Mott  (52)  showed  by  histological  study,  all  of  the  perivascular, 
pericapillary  and  perineuronal  spaces  are  dilated.  The  author  (68) 
made  use  of  this  phenomenon  as  a  means  of  injecting  this  perivascular 
system  from  the  subarachnoid  space.  The  second  of  these  conditions 
under  which  the  perivascular  flow  is  toward  nerve-cell,  is  brought  about 
by  the  intravenous  injection  of  strongly  hypertonic  solutions.  This 
phenomenon  was  first  noted  by  Weed  and  McKibben  (76)  who  supplied 
a  foreign  solution  of  sodium  ferrocyanide  and  iron-ammonium  citrate 
to  the  subarachnoid  space  at  the  time  when  the  cerebrospinal  fluid 
pressure  was  approaching  zero,  following  the  intravenous  injection  of  a 
strongly  hypertonic  solution.  This  foreign  solution  was  subsequently 
found  (p.  536)  "to  have  passed  from  the  subarachnoid  space  along  the 


200  LEWIS   H.    WEED 

perivasculars  into  the  substance  of  the  nervous  system,  reaching  the 
interfibrous  spaces  in  the  white  matter  and  the  pericellular  spaces  in 
the  gray."  These  observations  were  interpreted  as  indicating  that, 
under  the  influence  of  the  intravenous  injection  of  the  strongly  hyper- 
tonic  solution,  the  dislocation  of  a  considerable  quantity  of  cerebro- 
spinal  fluid  into  the  nervous  system  occurred. 

Foley  (29)  has  subsequently  carried  out  experiments  quite  similar  to 
those  reported  by  Weed  and  McKibben,  using  the  same  foreign  salts 
for  subarachnoid  introduction  and  intravenous  injections  of  strongly 
hypertonic  solutions.  In  addition  to  the  findings  already  detailed, 
Foley  obtained  evidence  of  a  retrograde  absorption  not  only  by  epen- 
dyma  but  by  choroid  plexuses.  The  absorption  by  the  ependyma  is 
amply  verified  by  the  work  of  Wislocki  and  Putnam  (79)  and  Nanagas 
(53),  but  these  latter  workers,  using  careful  histological  control,  have 
been  unable  to  obtain  evidence  of  absorption  of  the  foreign  salts  by 
the  choroid  plexuses. 

And  in  work  as  yet  unpublished  the  writer  has  repeated  many  of  his 
earlier  experiments  done  with  McKibben,  with  findings  confirmatory  in 
every  regard.  The  intracranial  vascular  and  the  cerebrospinal  fluid 
pressures  have  been  determined  both  before  and  throughout  the  period 
of  subarachnoid  introduction  of  the  foreign  solution,  so  that  definite 
physiological  control  is  afforded.  The  results  indicate  that  with  the 
increase  of  osmotic  pressure  of  the  blood,  due  to  the  intravenous  injec- 
tion of  hypertonic  solutions,  the  cerebrospinal  fluid  is  aspirated  into  the 
shrinking  nervous  system,  chiefly  along  the  perivascular  channels  but 
also  through  the  ependymal  lining  of  the  ventricles.  Along  these  chan- 
nels, under  this  extraordinary  osmotic  pull,  actual  absorption  of 
the  fluid  into  the  vessels  of  the  nervous  tissue  takes  place.  The 
findings  suggest  a  reversal,  following  the  injection  of  the  hypertonic 
solution,  of  the  normal  processes;  the  osmotic  pressure  of  the  blood 
stream,  under  these  conditions,  seems  to  be  a  determining  factor  in  the 
absorption  of  the  cerebrospinal  fluid.  Interpretation  of  certain  of  the 
experimental  observations  makes  it  seem  likely  that  diffusion  also  plays 
a  part  in  the  process. 

RESUME 

The  limitations  of  this  review  have  made  it  impossible  to  more  than 
rather  briefly  discuss  a  few  of  the  many  problems  connected  with  the 
cerebrospinal  fluid.  Many  equally  absorbing  phases  have  been 
untouched  for  one  or  another  reason  but  an  attempt  has  been  made  to 


THE    CEREBROSPINAL   FLUID  201 

indicate  the  type  of  evidence  which  has  furnished  the  working 'hypotheses 
and  to  point  out  the  limitations  of  the  procedures  on  which  so  many 
conclusions  have  been  based. 

Our  present  knowledge  of  the  processes  of  the  cerebrospinal  fluid  in 
many  respects  is  inadequate.  The  conception  that  this  characteristic 
body-fluid  is  largely  produced  by  the  intraventricular  choroid  plexuses 
is  based  not  on  any  single  conclusive  piece  of  evidence  but  on  a 
mass  of  suggestive  data;  when  considered  from  all  standpoints,  however, 
the  hypothesis  seems  today  well  established.  The  current  ideas  regard- 
ing the  circulation  of  the  fluid  through  cerebral  ventricles  and  sub- 
arachnoid  space  are  founded  largely  on  exact  anatomical  evidence, 
particularly  in  regard  to  the  structure  of  the  meninges  and  the  use  of 
these  intrameningeal  channels  as  fluid-pathways.  And  likewise,  there 
are  firm  and  reliable  data  of  an  anatomical  and  physiological  nature 
supporting  the  contention  that  the  cerebrospinal  fluid  is  absorbed 
largely  into  the  venous  system  and  to  a  lesser  extent  into  the  lymphatic 
channels.  It  is  possible  now  to  discard  the  hypothesis  of  equality  . 
between  the  cerebrospinal  fluid  pressure  and  that  of  the  cerebral  veins, 
and  to  regard  the  cerebrospinal  fluid  as  being  maintained  at  an  indi- 
vidual, relatively  independent  pressure  at  fairly  constant  levels  above 
that  of  the  sagittal  venous  sinus.  The  conceptions  of  pressure-changes 
effected  by  the  intravenous  injection  of  solutions  of  various  concentra- 
tions are  substantiated  by  dependable  observations,  but  it  does  not  seem 
as  yet  justifiable  to  accept,  without  further  control,  the  data  furnished 
in  regard  to  similar  changes  brought  about  by  administration  of  phar- 
macological agents  and  tissue  extracts.  And  the  same  cautions  may 
be  urged  in  regard  to  the  acceptance  of  conclusions  based  on  the  effects 
of  various  agents  upon  the  rate  of  outflow  of  the  fluid. 

Yet  these  problems  are  but  few  of  the  many  fascinating  subjects  of 
investigation  in  this  field.  The  interesting  questions  of  the  chemical 
composition  of  the  fluid  have  not  been  discussed:  is  the  cerebrospinal 
fluid  a  true  secretion,  a  transudate,  or  a  modified  dialysate?  Likewise, 
the  long-debated  problems  of  the  passage  of  foreign  salts,  of  drugs,  etc., 
from  blood  stream  into  the  fluid  must  be  left  for  future  review,  though 
with  possibly  a  note  of  suggestion  that  these  investigations  be  carried 
out  with  control  of  the  cerebrospinal  fluid  pressure.  And  so  may  the 
many  other  partially  answered  questions  centering  about  this  fluid  be 
enumerated. 

But  in  this  field  of  research  the  work  of  the  next  few  years  will  solve 
certain  problems;  yet  the  solution  of  these  will  but  expose  wider  fields 


202  LEWIS   H.    WEED 

for  examination.  Here,  as  in  countless  other  investigations,  the  study  of 
structure  must  proceed  hand  in  hand  with  the  study  of  "function, 
for  many  of  the  erroneous  conceptions  introduced  into  the  literature  of 
the  cerebrospinal  fluid  have  been  due  to  failure  to  give  regard  to  one  or 
other  of  these  basic  factors.  Future  investigations  will  be  the  more 
profitable  if  the  studies  be  largely  along  the  lines  of  physiological- 
anatomical  control. 

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